PROJECT SUMMARY This K01 will provide the applicant with training in support of becoming an independent, interdisciplinary researcher on the interplay among children?s biologically-informed genetic predispositions for behavioral disinhibition (impulsivity, sensation seeking, externalizing), negative family environments, and family-based prevention effects in pathways to early adolescent substance use. The applicant will accomplish this objective through (1) developing expertise in advanced genomic (e.g., genome-wide associations and meta-analysis) and bioinformatics methods (e.g., functional annotation, pathway and gene-network analyses) to create biologically-informed markers of genetic predisposition; and (2) gaining an interdisciplinary understanding of adolescent substance use across genetic, familial, and prevention domains. These goals will be accomplished through genomics and bioinformatics workshops, formal coursework in bioinformatics and substance use, and mentored instruction (including directed readings and supervised research experiences). Instruction will be complemented by professional development seminars, grant writing workshops, and training in the responsible conduct of research. Training will be accomplished at Arizona State University?s (ASU?s) School of Social and Family Dynamics and REACH Institute, with primary mentorship from Dr. Thomas Dishion (expert in family- based prevention of adolescent substance use). Co-mentorship will be provided by Dr. Laurie Chassin (expert in substance use etiology), Dr. Kathryn Lemery-Chalfant (expert in gene-environment interplay), and Dr. Valentin Dinu (expert in bioinformatics and genomics), and collaboration with Dr. Arpana Agrawal (expert in advanced genetic methods in substance use) and Dr. David MacKinnon (expert in causal mediation analyses). The first aim is to examine if biologically-informed genetic predispositions for behavioral disinhibition evoke and/or moderate negative family environments in predicting early adolescent substance use. It is hypothesized that genetic predisposition will be moderated by and evoke negative family environments, which will contribute to early adolescent substance use. The second aim is to examine if family-based prevention effects moderate genetic predispositions for behavioral disinhibition?or moderate genetically evoked negative family environments?in predicting early adolescent substance use. It is hypothesized that genetic predisposition will be moderated by prevention effects in predicting early adolescent substance use and that prevention effects will buffer the genetic evocation of negative family environments. Aims will be tested in the Early Steps (age 2? 15.5) and Project Alliance 1 (age 11?27) samples, which are large, genetically-sensitive longitudinal studies of familial and family-based prevention effects on adolescent substance use. Training in bioinformatics methods will be used to refine and create measures of biologically-informed genetic predisposition to examine gene- environment interplay. These training and research objectives address NIDA?s strategic plan to investigate gene-environment interplay in adolescent substance use and inform next generation interventions.